Switch On Your HIV Smarts.

Undetectable & Low-level HIV Viral Replication

Getting to “undetectable”—and staying there—is often the primary goal for people living with HIV. People who maintain undetectable viral loads (fewer than 50 copies of the virus per milliliter of blood) not only improve their own health but decrease the likelihood of transmitting HIV to sex partners. But taking the right medications and getting the right health care—while a large part of the equation—aren’t everything. Even people who are adherent to their medication regimens may experience occasional “blips” in their viral loads, experience viral rebound or maintain a steady, if low, viral load above undetectable levels.

This can be a source of confusion and fear. David Fawcell, PhD, LCSW recently chronicled the negative emotions he experienced after having his viral load unexpectedly climb from undetectable up into the 400s, then returned to levels just above detectable. “Not having the psychological (and medical) safety net of being “undetectable” has reawakened the looming uncertainty of living with HIV, that nagging concern about the future that I had shoved out of my consciousness while undetectable—made worse when I see others nonchalantly taking their undetectable status for granted,” he said.

To get some insight about getting and staying undetectable and why some people struggle to achieve or remain undetectable, we spoke with Keith Henry, MD, an HIV specialist at Hennepin County Medical Center who has more than 25 years of experience caring for people with HIV.

BETA: Let’s review—first, what is “undetectable”?

Dr. Keith Henry (Photo: Hennepin County Medical Center)

Dr. Keith Henry: Undetectable refers to a level of virus that’s so low that it can’t be measured—detected—by the viral load assay test. Usually, “undetectable” refers to a viral load that’s under 50 copies/mL. But different assays can detect the amount virus copies in the blood at different thresholds. Our lab can actually detect levels down to at least 20 copies/mL, but we intentionally report low levels as simply “less than 50.” At this point, there’s no clinical relevance if a person’s viral load is 20 at one visit and 40 at the next, so we don’t want patients (who can access their lab result via computer) to get worked up over changes in viral load at that level.

Let’s talk about instances of low-level viremia (low-level viral replication), between 50 and 500 copies/mL. Do you see people at your clinic with viral loads in this range, who have either been undetectable previously or never reached undetectable after beginning treatment?

Yes. And let me explain a few nuances here.

If a person was undetectable, then their viral load goes up once to a low level and then quickly goes back to being undetectable, that’s called a “blip.” Those can happen for all kinds of reasons, like if there’s a lapse in drug adherence. Blips can happen sometimes without any explanation, and they are not usually something we worry about if the person goes back to being undetectable.

Viral loads that stay in the range between 50 and 200 copies/mL are a bit more difficult to interpret. It might be that the person isn’t taking their ART daily, but there could be another reason the person doesn’t get or stay at an undetectable viral load level. I know at least one patient who is unbelievably adherent—he never misses doses. Every few visits to the clinic he’ll have a viral load that pops up between 50 and 200 copies/mL. It’s a bit of a puzzle why this happens.

People who experience sustained viral loads over 200 copies/mL are more of a concern. It’s more likely that they’re going to experience treatment failure—their medications will stop working to control their viral loads at all—and that they’ll develop a drug-resistant mutation.

Can you speculate about why a person who is 100% adherent would still have a detectable viral load?

If adherence isn’t the issue, there are a few different ideas about this low-level viremia. It could be that some regimens, typically composed of three drugs, aren’t fully suppressing replication of HIV. It could be that the medications aren’t penetrating—fully entering and working within—the body’s gut, lymphatic tissues, or central nervous system areas that are havens or reservoirs for HIV. Lymph tissue in HIV-infected patients is often very scarred, perhaps providing sanctuary to HIV deep with the tissues. Ongoing or bursts of inflammation may also contribute to activation of HIV within tissues that may spill out in to the blood stream where it is detected.

Drug resistance is another issue. We know that some drugs, like Atripla, are more likely to produce drug-resistant strains of HIV. Some drug regimens, like boosted protease inhibitors and dolutegravir, are less likely to cause drug resistance. So when we get viral rebound at levels high enough for us to look for drug resistance, we test for it.

If you find a drug-resistant mutation, what do you do? Do you change the person’s ART regimen?

If a person has a viral load that stays over 500 copies/mL, and they test positive for a resistance mutation, this would be evidence of treatment failure. I would, at this point, change the drug regimen.

But this is a difficult question to answer if someone’s viral load is steadily in that 200 to 500 copies/mL range. Here’s one reason why I think that:

A few years ago, our lab made a switch to a new type of assay that we used to run viral load tests. And suddenly—a lot of our patients that were suppressed were turning up with viral loads between 100 and 500 copies/mL. We did genotype testing to determine if people had developed drug resistance, and found that many had resistance to emtricitabine with the M184V mutation or efavirenz with the K103N mutation. Before we started to act on this new information, and switch people to new regimens, we switched our viral load test assay and testing procedure to one that we had more confidence in—and then most of those patients’ viral loads started coming back as undetectable.

This really surprised us. It’s possible that the assay we used to test resistance was detecting minority strains of HIV that were resistant—but that overall, they somehow weren’t able to populate the entire system so that people were still able to maintain low levels of virus in their blood.

But that’s why—before this happened—I would have automatically said that if you detect a resistance mutation at a low level of viremia, you need to switch the drug regimen. But because we found resistance mutations in people who eventually re-tested as undetectable, I’d say for me that’s it not so black and white. I’m not as dogmatic about changing drug therapy as soon as a resistance mutation is detected. Luckily now we have even more potent, simpler regimens such as boosted protease inhibitors and dolutegravir that have a high barrier to resistance so we see resistance to those drugs very rarely.

Are there any other reasons why people might get low-level viremia?

I always holistically assess everything patients put into their body. That includes food, over the counter medications and alternative medicines. I had a patient who was viremic and for a while we couldn’t figure out what was going on. It turned out that he started drinking a lot of grapefruit juice, and that was causing a decrease in the levels of his protease inhibitor. St. John’s wort, proton pump inhibitors and histamine-2 blockers like cimetidine can also affect the metabolism of some HIV medications.